Palladium-catalyzed methods for the formation of carbon-heteroatom bonds, e.g., carbon-nitrogen bonds, are now widely-exploited in the synthesis of pharmaceuticals, materials with important electronic properties, and ligands for early metal catalysts. See, e.g., Stille, J. K. Angew. Chem., Int. Ed. Engl., 25:508-524 (1986); Miyaura, N. et al., Chem. Rev., 95:2457-2483 (1995); Negishi, E. Acc. Chem. Res., 15:340-348 (1982). Likewise, the palladium-catalyzed coupling to form carbon-carbon bonds between an aryl or vinyl halide and a carbon nucleophile is widely used. However, the ever-increasing cost of palladium detracts from the allure of these powerful methods. Consequently, a need exists for general and efficient catalytic methods for forming carbon-heteroatom and carbon-carbon bonds based on a catalyst that does not comprise a rare, costly transition metal, such as palladium. Likewise, a need also exists for a general and efficient catalytic method for forming carbon-carbon bonds between an aryl or vinyl halide and a carbon nucleophile, based on a catalyst that does not comprise a rare, costly transition metal, such as palladium. Notably, in 1998, bulk palladium sold on the international metal market for roughly five-thousand times the cost of bulk copper. Therefore, based solely on catalyst cost, the aforementioned transformations would be orders of magnitude more appealing if they could be achieved with catalysts comprising copper rather than palladium.
Copper-Catalyzed Carbon-Sulfur Bond Formation
Aryl sulfides are an important class of compounds for biological, material and pharmaceutical applications. Liu, G.; Link, J. T.; Pei, Z.; Reilly, E. B.; Leitza, S.; Nguyen, B.; Marsh, K. C.; Okasinski, G. F.; von Geldern, T. W.; Ormes, M.; Fowler, K.; Gallatin, M. J. Med. Chem. 2000, 43, 4025-4040; Beard, R. L.; Colon, D. F.; Song, T. K.; Davies, P. J. A.; Kochhar, D. M.; Chandraratna, R. A. S. J. Med. Chem. 1996, 39, 3556-3563; Nagai, Y.; Irie, A.; Nakamura, H.; Hino, K.; Uno, H.; Nishimura, H. J. Med. Chem. 1982, 25, 1065-1070; Pinchart, A.; Dallaire, C.; Gingras, M. Tetrahedron Lett. 1998, 39, 543-546; Hay, A. S.; Ding, Y. Macromolecules 1997, 30, 1849-1850; Hay, A. S.; Wang, Z. Y.; Tsuchida, E.; Yamamoto, K.; Oyaizu, K.; Suzuki, F. Macromolecules 1995, 28, 409-415; Miki, H.; Nakahama, T.; Yokoyama, S.; Mashiko, S. U.S. Patent Application Publication US 20020072583 A1; Wang, Y.; Chackalamannil, S.; Chang, W.; Greenlee, W.; Ruperto, V.; Duffy, R. A.; McQuade, R.; Lachowicz, J. E. Bioorg. Med. Chem. Lett. 2001, 11, 891-894; Bonnet, B.; Soullez, D.; Girault, S.; Maes, L.; Landry, V.; Davioud-Charvet, E.; Sergheraert, C. Bioorg. Med. Chem. 2000, 8, 95-103; Sawyer, J. S.; Schmittling, E. A.; Palkowitz, J. A.; Smith III, W. J. J. Org. Chem. 1998, 63, 6338-6343. Traditional transition metal catalyzed methods for the construction of aryl-sulfur bonds usually require harsh reaction conditions; for example, the coupling of aryl halides with arenethiolate anion using Ni complexes requires high temperature (˜200° C.) and a strong base (NaH); besides, side products are commonly observed. Diederich, F.; Stang, P. J. Metal-catalyzed Cross-Coupling Reactions, Wiley-VCH 1998; Hassan, J.; Sévignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102, 1359-1470; Cristau, H. J.; Chabaud, B.; Chéne, A.; Christol, H. Synthesis 1981, 892-894.; Takagi, K. Chem. Lett. 1987, 2221-2224. Since Migita's report on palladium-catalyzed diaryl sulfide formation, only a few reports have appeared using palladium complexes as the catalysts, and the substrate scope is narrow. Migita, T.; Shimizu, T.; Asami, Y.; Shiobara, J.-i.; Kato, Y.; Kosugi, M. Bull. Chem. Soc. Jpn. 1980, 53, 1385-1389; Zheng, N.; McWilliams, J. C.; Fleitz, F. J.; Armstrong III, J. D.; Volante, R. P. J. Org. Chem. 1998, 63, 9606-9607; Harr, M. S.; Presley, A. L.; Thorarensen, A. Synlett. 1999, 1579-1581; Schopfer, U.; Schlapbach, A. Tetrahedron 2001, 57, 3069-3073; Li, G. Y. Angew. Chem. Int. Ed. 2001, 40, 1513-1516; Li, G. Y. J. Org. Chem. 2002, 67, 3643-3650; Ciattini, P. G.; Morera, E.; Ortar, G. Tetrahedron Lett. 1995, 36, 4133-4136; Ishiyama, T.; Mori, M.; Suzuki, A.; Miyaura, N. J. Organomet. Chem. 1996, 525, 225-23; Wendeborn, S.; Berteina, S.; Brill, W. K.-D.; Mesmaeker, A. D. Synlett. 1998, 671-675. Catalyst systems such as Pd(OAc)2/Tol-BINAP or Pd2(dba)3/DPPF allow to couple aryl triflates or aryl iodides only with alkyl thiols and not with aromatic thiols. In addition, they often require a strong base, e.g., NaOt-Bu, which is not compatible with base-sensitive functional groups.
An alternative coupling methodology, copper-catalyzed Ullmann-type coupling, is attractive for large and/or industrial-scale applications. Lindley, J. Tetrahedron 1984, 40, 1433-1456. However, a mild Cu-catalyzed C—S bond formation reaction compatible with a broad range of functional groups remains elusive. Palomo, C.; Oiarbide, M.; López, R.; Gómez-Bengoa, E. Tetrahedron Lett. 2000, 41, 1283-1286; Herradura, P. S.; Pendola, K. A.; Guy, R. K. Org. Lett. 2000, 2, 2019-2012; Kalinin, A. V.; Bower, J. F.; Riebel, P.; Snieckus, V. J. Org. Chem. 1999, 64, 2986-2987.
Copper-Catalyzed Cyanation of Aryl Halides
Aromatic nitrites are very important materials because of their wide application from small laboratory scale to industrial purposes. Since the first cyanation reaction of an aromatic halide was reported, various methods have been developed for the synthesis of aromatic nitrites involving the use of different metals in presence of cyanide sources. Pongratz, A. Monatsh. Chem. 1927, 48, 585; Pongratz, A. Monatsh. Chem. 1929, 52, 7; Ellis, G. P., Rommney-Alexander T. M. Chem. Rev. 1987, 87, 779.
The most convenient cyanation method is the stoichiometric reaction of aryl halides with copper(I) cyanide at high temperature (typically over 150° C.). Aromatic iodides, bromides, chlorides and fluorides are converted by copper(I) cyanide into the nitrites, the iodides being the most reactive. The difference in reactivity between aryl iodides and chlorides is sufficient to permit preferential cyanation of the iodide in presence of a chloride. Suzuki, H.; Hanafusa, T. Synthesis 1974, 53. Unfortunately, the product isolation is very troublesome due to the formation of different copper species in the course of the reaction.
Palladium-catalyzed displacement of aryl halides and triflates with cyanide ion to afford the corresponding aromatic nitrites has been reported as an alternative to the copper-catalyzed process. Sundermeier, M.; Zapf, A.; Beller, M.; Sans, J. Tetrahedron Lett. 2001, 42, 6707; Hioki, H.; Nakaoka, R.; Maruyama, A.; Kodama, M. J. Chem. Soc., Perkin Trans. 1 2001, 3265; Jiang, B.; Kan, Y.; Zhang A. Tetrahedron 2001, 57, 1581. Jin F.; Confalone, P. N.; Tetrahedron Lett. 2000, 41, 3271; Maligres, P. E.; Waters M. S.; Fleitz, F. Askin, D. Tetrahedron Lett. 1999, 8193; Sakamoto, T.; Oshwa, K. J. Chem. Soc. Perkin Trans. 1 1999, 2323; Anderson, B. A.; Bell, E. C.; Ginah, F. O.; Harn, N. K. ; Pagh, L. M.; Wepspiec, J. P. J. Org. Chem. 1998, 63, 8224. Nickel complexes can also catalyze the cyanation of aromatic halides or heteroaromatic halides into the corresponding aromatic cyanides under the influence of an alkali metal cyanide. Duphar International Research B. V, Nickel catalyst for the cyanation of aromatic halides, European Patent Application 0 613 719 A1, Jul. 9, 1994; Occidental Chemical Corporation, Cyanation of haloaromatics utilizing catalyst generated in situ starting with NiCl2 or NiCl2.6H2O, European Patent Application 0 384 392 A1; Sakakibara, Y.; Ido, Y.; Sasaki, K.Saki, M.; Uchino, M. Bull Chem. Soc. Jpn. 1993, 66, 2776-78; H. Lundbeck A/S, Method for the preparation of Citalopram by nickel-catalyzed cyanation of halo precursors, GB Patent 2 354 240 A1, Mar. 21, 2001; Teijin Ltd., Japan Preparation of 5-(3-cyanophenyl)-3-formylbenzoic acids as intermediates for factor Xa inhibitors. JP Patent 2001335551 A2, Dec. 4, 2001; Cassar, L.; Foa, M.; Montanari, F.; Marinelli, G. P. J. Organomet. Chem. 1979, 173, 335-9; Cassar, L. J. Organomet. Chem. 1973, 54, C57-C58. Alternative methods involving phase transfer catalysts or the presence of other activating agents have been recently reported. Yu-Qing, C.; Bao-Hua, C.; Ben-Gao, P. Synth. Commun. 2001, 31, 2203; Tamon, O.; Jitsuo, K.; Toyooka, Y. Chem. Lett. 1998, 5, 425; Aventis Cropscience GMBH, Process for the preparation of 2-cyanopyridines WO 01/17970 A1, Mar. 15, 2001; Mitsui Chemicals, Inc., Japan Process for producing substituted aromatic compound. WO 01/81274 A1, Nov. 1, 2001.
Copper-Catalyzed Halogen Exchange
Aryl and vinyl halides are widely used in organic synthesis to form carbon-carbon and carbon-heteroatom bonds in transition metal-catalyzed processes, such as the Heck, Stille, Suzuki and Ullmann-type coupling reactions. In these processes, aryl iodides are usually more reactive than the corresponding aryl bromides and uniformly more reactive than aryl chlorides, which often fail in cases where aryl iodides work well. Goldfinger, M. B.; Crawford, K. B.; Swager, T. M. J. Am. Chem. Soc. 1997, 119, 4578. In addition, 125I-radiolabelled aryl iodides find an important application in pharmacokinetic studies. Mertens, J.; Vanryckeghem, W.; Bossuyt, A. J. Labelled Compd. Radiopharm. 1985, 22, 89; Menge, W. M. P. B.; van der Goot, H.; Timmerman, H. J. Labelled Compd. Radiopharm. 1992, 31, 781.
Unfortunately, preparation of functionalized aryl iodides is relatively difficult. Merkushev, E. B. Synthesis 1988, 923. For example, iodination of arenes via diazonium salts (the Sandmeyer reaction) requires several steps. Iodination via metallated arenes can be problematic if the substrate contains electrophilic functional groups or acidic protons, both of which are incompatible with the metallated species. While direct iodination is facile in the cases of electron-rich arenes, highly reactive and expensive iodinating reagents are necessary to effect iodination of electron-poor arenes. Barluenga, J.; Gonzalez, J. M.; Garcia-Martin, M. A.; Campos, P. J.; Asensio, G. J. Org. Chem. 1993, 58, 2058; Olah, G. A.; Wang, Q.; Sanford, G.; Surya Prakash, G. K. J. Org. Chem. 1993, 58, 3194; Chaikovski, V. K.; Kharlova, T. S.; Filimonov, V. D.; Saryucheva, T. A. Synthesis, 1999, 748. Nevertheless, in certain circumstances, nickel- or copper-catalyzed halogen exchange reactions may be used to prepare aryl iodides from aryl bromides or chlorides despite several drawbacks. For example, the nickel-catalyzed halogen exchange usually results in partial conversion of the aryl halides, formation of biaryl sideproducts, and the reaction may require a stoichiometric amount of the nickel catalyst. Takagi, K.; Hayama, N.; Okamoto, T. Chem. Lett. 1978, 191; Takagi, K.; Hayama, N.; Inokawa, S. Bull. Chem. Soc. Jpn. 1980, 53, 3691; Tsou, T. T.; Kochi, J. K. J. Org. Chem. 1980, 45, 1930; Meyer, G.; Rollin, Y.; Perichon, J. Tetrahedron Lett. 1986, 27, 3497; Yang, S. H.; Li, C. S.; Cheng, C. H. J. Org. Chem. 1987, 52, 691; Bozell, J. J.; Vogt, C. E. J. Am. Chem. Soc. 1988, 110, 2655; Hooijdonk, M. C. J. M.; Peters, T. H. A.; Vasilevsky, S. F.; Brandsma, L. Synth. Commun. 1994, 24, 1261; Milne, J. E.; Jarowicki, K.; Kocienski, P. J. Synlett 2002, 607. The corresponding copper-catalyzed process traditionally requires high temperatures (>150° C.), polar solvents (DMF or HMPA), and a large excess of both copper(I) iodide and potassium iodide. Suzuki, H.; Kondo, A.; Inouye, M.; Ogawa, T. Synthesis 1985, 121; Suzuki, H.; Kondo, A.; Ogawa, T. Chem. Lett. 1985, 411; Clark, J. H.; Jones, C. W. Chem. Commun. 1987, 1409; Suzuki H.; Aihara, M.; Yamamoto, H.; Takamoto, Y.; Ogawa, T. Synthesis 1988, 236.